Report of the NIH Panel To Define Principles of Therapy of HIV Infection

Repair of Immune System Function May Be Incomplete Following Effective Inhibition of Continuing HIV Replication and Damage By Antiretroviral Drug Therapy

As discussed in the preceding principles, disease progression in HIV-infected patients results from active virus replication that inflicts chronic damage upon the function of the immune system and its structural elements, the lymphoid tissues. Because of the clonal nature of the antigen-specific immune response, in the absence of generation of immunocompetent CD4+ T cells from immature progenitor cells, it is likely that T cell responses may not be regained once lost, even if new rounds of HIV infection can be stopped by effective antiretroviral therapy.^(80,82,101) Similarly, it is not known if the damaged architecture of the lymphoid organs seen in persons with moderate to advanced HIV disease can be repaired following antiretroviral drug therapy. Should the residual proliferative potential of CD4+ and CD8+ T cells decline with increased duration of HIV infection and the magnitude of the cumulative loss and regeneration of lymphocyte populations, late introduction of antiretroviral therapy may have limited ability to reconstitute levels of functional lymphocytes. Thus, it is believed that the initiation of antiretroviral therapy before extensive immune system damage has occurred will be more effective in preserving and improving the ability of the HIV-infected person to mount protective immune responses.

Few reliable methods are now available to assess the integrity of immune responses in humans. However, the application of specific methods to the study of immune responses in HIV-infected patients before and after initiation of antiretroviral therapy indicates that immunologic recovery is incomplete even when HIV replication falls to undetectable levels. CD4+ T cell levels do not return to the normal range in most antiretroviral drug-treated patients, and the extent of CD4+ T cell increase is typically more limited when therapy is started in the later stages of HIV disease.⁽⁸²⁾ Recent evidence indicates that the repertoire of antigen-specific CD4+ T cells becomes progressively constricted with declining T cell numbers.⁽⁸²⁾ In persons who have evidence of a restricted T cell repertoire, antiretroviral therapy can increase total CD4+ T cell numbers but fails to increase the diversity of antigen recognition ability.⁽⁸²⁾ It is not yet known if expansion of a constricted CD4+ T cell repertoire of antigen recognition might be seen with longer-term follow-up of such persons.

Reports of OIs occurring in antiretroviral-treated patients at substantially higher CD4+ T cell counts than those typically associated with susceptibility to the specific opportunistic infections raise the concern that restoration of protective immune responses may be incomplete, even when effective suppression of continuing HIV replication is achieved.⁽¹⁰²⁾ However, other reports describe instances in which the clinical symptoms or signs of preexisting OIs were ameliorated,^(103-105) or in which new inflammatory responses to preexisting, but subclinical, OIs became manifest following initiation of effective combination antiretroviral therapy.^(106,107) These observations indicate that some improvement in immune function may be possible, even in patients who have advanced HIV disease, if sufficient numbers of pathogen-specific CD4+ T cells are still present when effective antiretroviral therapy is begun. The extent to which antiretroviral therapy can restore immune function when initiated in persons at varying stages of HIV disease is currently unknown but represents an essential question for future research.